Cannabinoids, such as d9-THC, affect the brain by activating G-protein coupled CB1 receptors that can inhibit adenylate cyclase, modulate a variety of ion channels, and inhibit synaptic transmission. These receptors are expressed widely throughout the brain, with particularly high levels of expression found in the cerebellum, the cortex, the hippocampus and the striatum. Recent studies provide new insight into the physiological role of the cannabinoid system and suggest that cannabinoids can act as retrograde messengers. Elevations of calcium in the dendrites of some types of neurons result in the cleavage of phospholipids leading to the formation and liberation of endogenous cannabinoids, which bind to presynaptic CB1 receptors to inhibit synaptic transmission. This retrograde inhibition lasts for tens of seconds. Our primary goal is to clarify the properties and mechanisms of this retrograde inhibition and to determine its physiological role. Studies will be performed in rodent cerebellar brain slice on excitatory and inhibitory synapses that are known to be retrogradely inhibited by cannabinoids released from Purkinje cell dendrites. These synapses are well suited to these studies because cells are readily identified, whole cell voltage clamp is straight forward, and both presynaptic and postsynaptic calcium levels can be monitored optically. Mechanistic studies will concentrate on the calcium dependence of cannabinoid release, identification of the presynaptic targets of that modulation, and determination of the factors governing its time course. Factors governing the spread of retrograde inhibition to synapses onto neighboring cells and its spatial extent will also be determined. In addition, we will determine the physiological role of retrograde inhibition in controlling synaptic strength and determine if it is a mechanism that can provide synapse-specific regulation or if it provides a homeostatic mechanism for a cell to regulate all of the synaptic inputs it receives. These basic mechanistic studies promise to help cannabinoids realize their great therapeuptic potential as an appetite stimulant, as an anticonvulsant, and in the treatment of Huntington's disease and Parkinson's disease.